Opposing activities of two novel members of the IL-1 ligand family regulate skin inflammation

The interleukin (IL)-1 family members IL-1α, -1β, and -18 are potent inflammatory cytokines whose activities are dependent on heterodimeric receptors of the IL-1R superfamily, and which are regulated by soluble antagonists. Recently, several new IL-1 family members have been identified. To determine the role of one of these family members in the skin, transgenic mice expressing IL1F6 in basal keratinocytes were generated. IL1F6 transgenic mice exhibit skin abnormalities that are dependent on IL-1Rrp2 and IL-1RAcP, which are two members of the IL-1R family. The skin phenotype is characterized by acanthosis, hyperkeratosis, the presence of a mixed inflammatory cell infiltrate, and increased cytokine and chemokine expression. Strikingly, the combination of the IL-1F6 transgene with an IL1F5 deficiency results in exacerbation of the skin phenotype, demonstrating that IL-1F5 has antagonistic activity in vivo. Skin from IL1F6 transgenic, IL1F5^−/− pups contains intracorneal and intraepithelial pustules, nucleated corneocytes, and dilated superficial dermal blood vessels. Additionally, expression of IL1RL2, -1F5, and -1F6 is increased in human psoriatic skin. In summary, dysregulated expression of novel agonistic and antagonistic IL-1 family member ligands can promote cutaneous inflammation, revealing potential novel targets for the treatment of inflammatory skin disorders.     

Islet Transplantation for Brittle Type 1 Diabetes: The UIC Protocol

This prospective phase 1/2 trial investigated the safety and reproducibility of allogeneic islet transplantation (Tx) in type I diabetic (T1DM) patients and tested a strategy to achieve insulin-independence with lower islet mass. Ten C-peptide negative T1DM subjects with hypoglycemic unawareness received 1–3 intraportal allogeneic islet Tx and were followed for 15 months. Four subjects (Group 1) received the Edmonton immunosuppression regimen (daclizumab, sirolimus, tacrolimus). Six subjects (Group 2) received the University of Illinois protocol (etanercept, exenatide and the Edmonton regimen). All subjects became insulin- independent. Group 1 received a mean total number of islets (EIN) of 1460   080 ± 418   330 in 2 (n = 2) or 3 (n = 2) Tx, whereas Group 2 became insulin- independent after 1 Tx (537   495 ± 190   968 EIN, p = 0.028). All Group 1 subjects remained insulin free through the follow-up. Two Group 2 subjects resumed insulin: one after immunosuppression reduction during an infectious complication, the other with exenatide intolerance. HbA1c reached normal range in both groups (6.5 ± 0.6 at baseline to 5.6 ± 0.5 after 2–3 Tx in Group 1 vs. 7.8 ± 1.1 to 5.8 ± 0.3 after 1 Tx in Group 2). HYPO scores markedly decreased in both groups. Combined treatment of etanercept and exenatide improves islet graft function and facilitates achievement of insulin-independence with less islets .     

Klinische und radiologische Ergebnisse nach bipolarer Radiuskopfprothese

Background

Radial head arthroplasty is considered to be the treatment of choice in non-reconstructable radial head fractures in the acute fracture situation. Despite the promising short-term results in the current literature, replacement of the radial head remains controversially discussed as long-term results are still missing. In our study, we report our 7.8-year results after treatment with the bipolar radial head prosthesis of Judet.

Materials and methods

Between 1997 and 2004, 34 patients were treated with Judet??s bipolar radial head prosthesis in our department. After a mean of 94 months (range 15?C139), 28 of these 34 patients could be re-examined. While 20 patients were treated with radial head arthroplasty primarily in a fracture situation, 7 patients were treated secondarily after failure of fixation. One patient was treated for a tumor of the proximal radius.

Results

According to the Mayo Elbow Performance Score, 16 patients achieved an excellent, 10 patients a good, 1 patient a fair, and 1 patient a poor result. The mean Disabilities of the Arm, Shoulder and Hand Questionnaire (DASH) score was 12.0 (range 0?C50.1). There was no distinct difference between primary and secondary implantation in terms of the clinical outcome. The elbow flexion averaged 125° (range 100?C150°); the mean extension deficit was 20° (range 0?C60°). The mean pronation was 66° (range 0?C90°) with a mean supination of 67° (range 0?C90°). The most common complications were osteoarthritis of the ulnohumeral joint (n=18) and degenerative changes of the humeral capitellum with erosions (n=12). Finally, 3 patients suffered a dislocation after the surgical intervention, 1 patient had an infection, and 1 patient developed a radioulnar synostosis.

Conclusion

Despite major primary complications and the high incidence of radiographic signs of degenerative changes, mainly good clinical results were achieved after 7.8 years with Judet??s bipolar prosthesis.     

Repositionstechniken in der Marknagelosteosynthese

Die Unfallchirurgie - Die Marknagelung wurde ursprünglich für die Stabilisierung von Schaftfrakturen der langen Röhrenknochen entwickelt. Neue Nageldesigns und multiple...     

Humeral nailing revisited

Unreamed interlocked humeral nailing for stabilisation of acute humeral fractures was introduced a decade ago. Antegrade and retrograde nail insertion are equally popular. The role of nailing as opposed to plating of humeral fractures is the subject of continuous debate. Between 1997 and 2005, 99 acute fractures of the humeral shaft were treated operatively with the unreamed humeral nail (UHN, Synthes) in our Level I Trauma Centre. The mean age of the patients was 63 years. Only eight patients (8.1%) were polytraumatised, nine patients had an open fracture (9.1%), five had a primary radial nerve palsy (5.1%). There were 54 antegrade and 45 retrograde nailings. The procedures were performed by 19 different surgeons, who carefully followed a detailed operation protocol. There were 6 adverse events: 3 secondary radial nerve palsies (3%), 2 fissures at the insertion point (2%) and one false placement of a locking screw (1%). Three patients developed pseudarthrosis (3%). Eight further operation were necessary (8.1%): 3 exploration of the radial nerve, 3 for treatment of pseudarthrosis, one replacement of a locking screw and one wound revision for superficial wound infection. Ninety patients (92 fractures) were evaluated after bone healing. Shoulder function was assessed using the Constant Score, elbow function with the Mayo Elbow Score. 91.3% and 5.4% of patients had an excellent or good shoulder function, 81.5% and 14.1% had an excellent or good elbow function. All patients with a functional deficit of the shoulder joint had antegrade, all patients with a deficit at the elbow joint retrograde nailing. Motor function recovered in all radial nerve palsies. 93.5% of patients had an excellent or good functional end result.Unreamed humeral nailing is a valid therapeutic option for stabilisation of acute humeral shaft fractures. Antegrade and retrograde nailing are associated with specific but different complications. By strictly adhering to the operation technique, the number and severity of complications can be reduced. When good fracture alignment and stability are obtained, uneventful bone healing with good functional outcome is the rule.     

Cutaneous manifestations of Corynebacterium jeikeium sepsis

Corynebacterium jeikeium is a rare but increasingly important cause of septicemia in neutropenic patients that can present with characteristic cutaneous findings. A 61-year-old man with myelodysplastic syndrome developed C. jeikeium sepsis and an erythematous papular eruption while neutropenic from induction chemotherapy. A review of the English language literature shows only six reported cases of hemorrhagic or erythematous papular eruption in C. jeikeium sepsis. The case is presented with an updated literature review of the history, risk factors, and treatment.     

Fibroblast and endothelial apoptosis in systemic sclerosis

PURPOSE OF REVIEW: Systemic sclerosis is a disease characterized by vascular and skin changes associated with activation of fibroblasts and increased synthesis of matrix components. These abnormalities lead to fibrosis and impaired function of internal organs such as the lung, kidney, and gastrointestinal tract. Recent evidence suggests that although activation of cells in and around the blood vessels and in the skin occurs in systemic sclerosis, injury to the vascular endothelium and defective apoptosis of skin fibroblasts may also contribute to disease. The purpose of this review is to discuss these findings in the context of the pathophysiology of systemic sclerosis. RECENT FINDINGS: This review highlights concepts and recent findings relating to apoptosis of vascular endothelium and skin fibroblasts. Important paradigms of fibroblast cell death in wound healing and keloid formation are discussed. Recent observations describing resistance of systemic sclerosis fibroblasts to Fas-mediated apoptosis and activation of the antiapoptotic protein kinase, Akt, are mentioned as possible contributors to fibroblast selection in this disease. SUMMARY: Improved understanding of how death and survival signals affect vascular endothelial cells and skin and visceral fibroblasts will lead to new approaches to therapy.     

Scleroderma fibroblasts demonstrate enhanced activation of Akt (protein kinase B) in situ

Recent studies suggest that, in addition to activation and hypersecretion of matrix components, fibroblasts from patients with systemic sclerosis (SSc) are relatively resistant to apoptosis. Transforming growth factor-beta (TGF)-beta is strongly implicated in the pathogenesis of SSc and we and others have shown that TGF-beta can activate Akt, a kinase with potent anti-apoptotic effects. To determine whether Akt was activated in SSc, we quantified phospho-Akt expression in skin fibroblasts in vitro by western blot analysis and a functional kinase assay. In addition, the relative proportion of fibroblasts containing activated Akt in was quantified by immunohistochemistry on skin sections insitu. Analysis of Akt phosphorylation of skin fibroblasts in vitro suggested increased phosphorylation of Akt, and evaluation of skin sections by immunohistochemistry revealed significantly higher percentages of fibroblasts that stained for phospho-Akt compared with controls (78% +/- 14.0% vs 13% +/- 9%, p < 0.001). In addition, co-incident staining of phospho-Akt and alpha-smooth muscle actin was observed in some fibroblasts. These findings indicate that Akt is activated insitu in skin fibroblasts from patients with SSc. Akt activation may contribute to resistance to apoptosis, selection of disease-inducing fibroblasts, and, possibly, myofibroblasts.     

Profilaggrin requires both linker and filaggrin peptide sequences to form granules: implications for profilaggrin processing in vivo.

Filaggrin is an intermediate filament associated protein that aids the packing of keratin filaments during terminal differentiation of keratinocytes. Premature aggregation of keratin filaments is prevented by filaggrin expression as the inactive precursor, profilaggrin, which is localized in keratohyalin granules in vivo. Profilaggrin is phosphorylated and contains multiple filaggrin repeats separated by a hydrophobic linker peptide. We have previously shown that filaggrin constructs containing the linker, when transiently transfected into epithelial cells, lead to expression of a protein that resembles keratohyalin (Dale et al. J Invest Dermatol 108:179-187 1997). To characterize further the region(s) of the linker and/or filaggrin that are necessary for granule formation, we generated several mutant constructs from Flag-FG-1, and generated fusions of filaggrin with green fluorescent protein. We also subjected profilaggrin to protein phosphatase 2A treatment and measured its subsequent solubility. We found that granular morphology is not dependent on the linker or conserved phosphorylation sites, nor is solubility affected by protein phosphatase 2A treatment. Granule morphology was abrogated only in a truncated construct, which still contains the linker. A construct consisting of 16 amino acids of filaggrin fused to green fluorescent protein led to rounded and bizarrely shaped transfected cells with compact keratin filaments, suggesting that very little filaggrin sequence is required for keratin filament interaction. Radiolabeled filaggrin-green fluorescent protein constructs specifically bound keratin in overlay assays confirming that the observed cytoskeletal collapse is due to filaggrin-keratin interaction. Our findings indicate that profilaggrin must be extensively processed before it loses both its granule forming ability as well as its insolubility, suggesting that granule formation in vivo correlates with insolubility in vitro. Further, filaggrin retains its ability to bind keratin as it is degraded to smaller peptides.